Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling

Chae Ryun Lee, Jung Nyeo Chun, Sang Yeob Kim, Soonbum Park, Su Hwa Kim, Eun Jung Park, In San Kim, Nam Hyuk Cho, In Gyu Kim, Insuk So, Tae Woo Kim, Ju Hong Jeon

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    Abstract

    Cyclosporin A (CsA) has antitumor effects on various cancers including prostate cancer. However, its antitumor mechanism is poorly understood. In this study, we showed that AMP-activated protein kinase (AMPK) mediates the antitumor effect of CsA on prostate cancer cells. CsA attenuated cell growth by inducing a G1 arrest through the inhibition of mTOR complex 1 (mTORC1) signaling. In this context, Akt was paradoxically activated downstream of the EGF receptor (EGFR)-mediated increase in phosphatidylinositol 3,4,5-trisphosphate (PIP 3) production. However, CsA also caused a Ca 2+/calmodulin- dependent protein kinase kinase β (CaMKKβ)-dependent activation of AMPK, which inhibits mTORC1 signaling; this led to ineffective Akt signaling. An EGFR or Akt inhibitor increased the growth suppressive activity of CsA, whereas the combination of an AMPK inhibitor and CsA markedly rescued cells from the G1 arrest and increased cell growth. These results provide novel insights into the molecular mechanisms of CsA on cancer signaling pathways.

    Original languageEnglish
    Pages (from-to)425-431
    Number of pages7
    JournalBiochemical Pharmacology
    Volume84
    Issue number4
    DOIs
    Publication statusPublished - 2012 Aug 15

    Bibliographical note

    Funding Information:
    This research was supported by the National Research Foundation of Korea (NRF) funded by the Korea Government (MEST) ( 2009-0086652 , 2010-0019472 , and 2010-0021234 ).

    Keywords

    • AMPK
    • Akt
    • Cyclosporin A
    • Prostate cancer
    • mTOR

    ASJC Scopus subject areas

    • Biochemistry
    • Pharmacology

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